Neuronal degeneration and death normally occur during development and result in the elimination of cells which fail to make crucial inter-neural or neuro-muscular contacts. Neuronal degeneration and death also occur during senescence and as a result of pathological events (e.g., infections, acute trauma) and some genetic diseases (e.g., Huntington's disease).
Neurotrophic factors are a group of proteins that can regulate the survival, development, differentiaiton and many of the functions of neuronal cells. Several neurotrophic factors have been described including members of the NGF-family of neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BNGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), and members of the IL-6 family, including interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin-M (OSM). The discovery of neurotrophic factors lead to the possibility that these factors could be administered to mammals as therapeutic agents to treat or prevent neuronal degeneration. However, the proteins which have been identified as neurotrophic factors generally mediate multiple biological functions (e.g., immune regulation, hematopoiesis). Thus, the ability to safely administer neurotrophic factors to mammals is severely limited due to undesirable side effects. For example, the administration of CNTF can result in muscle atrophy, cachexia and anorexia (Martin, D., et al., Am. J. Physiol. 271: 1422–1428 (1996)).
One example of an infectious disease which leads to neuronal degeneration is Chagas' disease, which is produced by the obligate intracellular protozoan Tyrpanosoma cruzi. This disease is an important cause of cardiac and gastrointestinal (GI) morbidity and mortality in millions of people in Latin America. The disease is usually transmitted to man by infected reduviid bugs or by blood transfusion. For a few months parasites circulate in the bloodstream as a result of their invasion of, and rapid replication in a variety of cell types, particularly muscle cells in the heart and GI tract, and glial cells in the nervous system (acute infection). Most patients survive the acute infection to enter a subclinical, asymptomatic stage that lasts years to decades (the indeterminate phase). The vast majority of patients in the indeterminate phase (˜90%) show no signs of peripheral neuropathy (Genovese, O., et al., Arq. Neuropsiquiatr 54: 190–196 (1996)). In fact, the average numbers of both cardiac and GI ganglia actually increase with the age of the chagasic patient (Köberle, F. Adv. Parasitol. 6: 63–71 (1968)).
The relative increase in the number of neuronal cells observed in infected individuals is dramatically different from the age-related physiological reduction in the number of cells found in ganglia of normal uninfected individuals (Köberle, F. Adv. Parasitol. 6: 63–71 (1968); Meciano Filho, J. Gerantology 41. 18–21 (1995)). The neuroprotective/neuroproliferative effect of T. cruzi infection in humans, is consistent with histological and electrophysiological findings in laboratory animals infected with the trypanosome. For example, infected mice showed signs of neuron development, axon regeneration and axon sprouts, in addition to some neuron degeneration. Furthermore, studies with rats infected with T. cruzi provide pharmacological evidence for axonal regrowth and sprouting in sympathetic and parasympathetic nerve fibers of the heart and colon (Machado, C. R., et al., Am. J, Trop. Med. Hyg. 27: 20–24 (1978); Machado, C. R., et al., Braz. J. Med. Biol. Res. 20: 697–702 (1987)).
In contrast to indeterminate phase, extensive destruction of the autonomous nervous system in the heart and GI tract occurs in individuals with chronic Chagas' disease. Histologically, the neurons in the heart are shrunk and disintegrated, with or without perineural and intraneural inflammation. This neurological pathology likely contributes to the generation of cardiomegaly (Mott, K. E. and Hagstrom, J. W. C., Cicrulcation 31: 273–286 (1965); Oliveira, J. S. M., et al., Am. Heart J. 109: 304–308 (1985)). In the GI tract, myenteric (Auerbach's) and submucosal (Meissner's) ganglia can be more than 95% destroyed (Köberle, F. Adv. Parasitol. 6: 63–71 (1968)). This neuronal destruction provides one explanation for the tremendous enlargement of the esophagus and colon (megaesophagus and megacolon) of chronic Chagas' disease (Köberle, F. In Ciba Foundation Symposium 20: 137–147 (1974)).
The biochemical pathways that rescue neurons from death in the indeterminate phase are unknown, as are the pathways that drive neurons to die in the chronic disease. An intriguing possibility is that T. cruzi secretes a factor(s) that promote(s) development and survival of neurons. Such a factor(s) could help neurons counterbalance neurotoxic insults resulting from the infection process.
A need exists for a method of providing neurotrophic support in a mammal, and for neurotropic factors which significantly reduce or eliminate the above-mentioned problems.